1. Field of the Invention
The present invention relates generally to the fields of gene delivery vectors and gene therapy. More specifically, the present invention relates to lentiviral vectors useful in human gene therapy for inherited and proliferative ocular disease.
2. Description of the Related Art
One of the most common causes of human blindness is abnormal, intraocular cellular proliferation that often results in a loss of clarity of the visual axis or in a separation of the retina from the retinal pigment epithelium due to tractional forces applied directly to the retinal surface. Proliferative retinal detachment, whether it is related to proliferative diabetic disease, retinopathy of prematurity, proliferative vitreoretinopathy, or neovascular age-related muscular degeneration, ultimately will result in permanent loss of vision if left untreated.
The abnormal proliferation of new blood vessels within the eye, ocular neovascularization, is the most common cause of permanent blindness in developed countries. Three diseases are associated with the vast majority of all cases of intraocular neovascularization, namely diabetes, retinopathy of prematurity and age-related muscular degeneration. While these three clinical entities are distinct and affect different groups of patients, they share a final common pathway that involves uncontrolled division of endothelial cells leading to formation of new blood vessels that ultimately compromise retinal function. Ocular proliferative diseases affect 7% of the U.S. population and leads to annually 25,000 new cases of blindness in the United States. For people over 65 years old in the United States, 30% are affected by the diseases.
Proliferation of vascular endothelial cells within the retina initiates the process of proliferative diabetic retinopathy (PDR). If untreated, these endothelial cells continue to divide and eventually form fibrovascular membranes that extend along the inner surface of the retina or into the vitreous cavity. Contraction of the posterior vitreous surface results in traction at the sites of vitreo-fibrovascular adhesions and ultimately detaches the retina. Approximately 50% of Type 1 diabetics will develop PDR within 20 years of the diagnosis of diabetes, whereas 10% of patients with Type 2 disease will evidence PDR within a similar timeframe.
Blood vessels usually develop by one of two processes: vasculogenesis or angiogenesis. During vasculogenesis, a primitive network of capillaries is established during embryogenesis by the maturation of multipotential mesenchymal progenitors. In contrast, angiogenesis refers to a remodeling process involving pre-existing vessels. In angiogenesis new vascular buds emanate from older, established vessels and invade the surrounding tissue. In the retina, once the normal vascular network is established, the remodeling of this network is largely under the influence of tissue oxygen concentration. Hypoxia (oxygen paucity) stimulates angiogenesis. It is this process which results in blindness in millions of diabetics, premature infants or the aged in our society.
Current treatments for intraocular neovascular diseases are invasive and destructive. The treatments frequently require intraocular surgery that is associated with the death of some tissues. Thus there is a need for new approaches to treat these diseases, and it is of interest to determine whether genes that modulate angiogenesis can be introduced into the eye to control the proliferative diseases. Currently it is difficult to perform gene transduction in mammalian cells with great degree of effectiveness. Results seen with traditional vectors such as adenoviral vectors, liposomes and dendrimer-based reagents are quite transient. It is also problematic to introduce these vectors into the eye without induction of a strong inflammatory response.
In order to mediate gene transfer to cells and tissues of the eye, the ideal gene delivery vector should have broad tropism and be able to transduce quiescent cells. The vector also needs to maintain sustained and robust transgene expression for the treatment of chronic diseases. Presently, there is a lack of means of transducing terminally differentiated or proliferating human cells within or derived from the eye. The present invention fulfills this long-standing need and desire in the art.